X-ray imaging is a well known and extremely valuable tool for the early detection and diagnosis of various disease states in the human body. The use of contrast agents for image enhancement in medical x-ray imaging procedures is widespread. An excellent background on contrast agents and media in medical imaging is provided by D. P. Swanson et al., Pharmaceuticals in Medical Imaging, 1990, MacMillan Publishing Company.
Briefly, in x-ray imaging, transmitted radiation is used to produce a radiograph based upon overall tissue attenuation characteristics. X-rays pass through various tissues and are attenuated by scattering, i.e., reflection or refraction or energy absorption. However, certain body organs, vessels and anatomical sites exhibit so little absorption of x-ray radiation that radiographs of these body portions are difficult to obtain. To overcome this problem, radiologists routinely introduce an x-ray absorbing medium containing a contrast agent into such body organs, vessels and anatomical sites.
Maximum enhancement of major blood vessels takes place during the so-called vascular phase of contrast media kinetics which occurs within about the first two minutes following the intravascular infusion or bolus injection of the contrast media. This is because the plasma concentration of an intravascular contrast medium decreases rapidly as a result of vascular mixing, transcapillary diffusion of the medium from the circulation into the interstitial spaces and renal excretion. Consequently, imaging of blood vessels must take place within a narrow time window, typically within a few minutes after infusion or injection of the x-ray contrast agent.
It would be desirable to provide improved x-ray contrast compositions for imaging vessels, anatomical sites and body organs such as the liver and spleen. Moreover, it would be highly desirable to provide intravenously administered x-ray contrast compositions which demonstrate effective imaging of the blood pool for extended periods of time.
Surface modified crystalline nanoparticles of water-insoluble x-ray contrast agents provide images of exceptional resolution and can be formulated for enhanced delivery to specific tissue or fluid sites, e.g., the blood pool, liver, kidney, bone marrow, lymph nodes and spleen. Moreover, preferred x-ray contrast agents when administered intravenously provide effective imaging of the blood pool within the vascular system for remarkably long periods of time.
Nanoparticles were first described in U.S. Pat. No. 5,145,684. These particles consist of a crystalline drug substance having a surface modifier adsorbed on the surface of the particles such that the average particle size is less than about 400 nm.
Iodine-containing agents in the nanoparticulate form dispersed with only Tetronic surfactant T-908 can remain in the blood pool for hours and give satisfactory imaging results.
However, in order to achieve autoclave sterilization of the suspension, an anionic surfactant such as dioctylsulfosuccinate (DOSS) or anionic phospholipid such as dimyristoylphosphatidylglycerol (DMPG) is often required. However, the charges imparted by the ionic surfactant/phospholipid lead to faster excretion of the drug substance and poor imaging results.
The blood residence time of intravenously injected nanoparticles is inversely related to the zeta potential of the nanodispersion. Nanoparticles with strong zeta potential tend to be cleared from the blood sooner, presumably by the reticuloenodthelial system (RES) system.
To overcome this charge effect, the zeta potential of nanoparticles dispersed with various surfactants, including those of the Tetronic series, were tested. It was noticed that the zeta potentials of nanoparticles dispersed with the Tetronic series of surfactants in the presence of DOSS or DMPG are inversely related to the molecular weight of the surfactants, i.e. higher molecular weight surfactants showed lower (absolute value) of zeta potentials and thus stronger ability to mask the charges on the particle.
These results led to the concept of using higher molecular weight surfactant to overcome the charge effect imparted by the ionic species added to the formulation. When tested with ethyl 3,5-diacetoamido-2,4,6-triiodobenzoate (WIN-8883), T-1508, the highest molecular weight surfactant in the Tetronic series, gave the lowest zeta potential nanoparticles in the presence of either DOSS or DMPG.